JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 67, NO.

1, 2016

ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER http://dx.doi.org/10.1016/j.jacc.2015.10.044

ORIGINAL INVESTIGATIONS

Exercise-Based Cardiac Rehabilitation

for Coronary Heart Disease
Cochrane Systematic Review and Meta-Analysis

Lindsey Anderson, PHD,* Neil Oldridge, PHD,y David R. Thompson, PHD,z Ann-Dorthe Zwisler, MD,x
Karen Rees, PHD,k Nicole Martin, MA,{ Rod S. Taylor, PHD*

ABSTRACT

BACKGROUND Although recommended in guidelines for the management of coronary heart disease (CHD),
concerns have been raised about the applicability of evidence from existing meta-analyses of exercise-based cardiac
rehabilitation (CR).

OBJECTIVES The goal of this study is to update the Cochrane systematic review and meta-analysis of exercise-based
CR for CHD.

METHODS The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, and Science Citation Index
Expanded were searched to July 2014. Retrieved papers, systematic reviews, and trial registries were hand-searched.
We included randomized controlled trials with at least 6 months of follow-up, comparing CR to no-exercise controls
following myocardial infarction or revascularization, or with a diagnosis of angina pectoris or CHD defined by angiog-
raphy. Two authors screened titles for inclusion, extracted data, and assessed risk of bias. Studies were pooled using
random effects meta-analysis, and stratified analyses were undertaken to examine potential treatment effect modifiers.

RESULTS A total of 63 studies with 14,486 participants with median follow-up of 12 months were included. Overall, CR
led to a reduction in cardiovascular mortality (relative risk: 0.74; 95% confidence interval: 0.64 to 0.86) and the risk of
hospital admissions (relative risk: 0.82; 95% confidence interval: 0.70 to 0.96). There was no significant effect on total
mortality, myocardial infarction, or revascularization. The majority of studies (14 of 20) showed higher levels of health-
related quality of life in 1 or more domains following exercise-based CR compared with control subjects.

CONCLUSIONS This study confirms that exercise-based CR reduces cardiovascular mortality and provides important
data showing reductions in hospital admissions and improvements in quality of life. These benefits appear to be
consistent across patients and intervention types and were independent of study quality, setting, and publication date.
(J Am Coll Cardiol 2016;67:1–12) © 2016 by the American College of Cardiology Foundation.

From the *Institute of Health Research, University of Exeter Medical School, Exeter, United Kingdom; yCollege of Health Sciences,
University of Wisconsin-Milwaukee, Milwaukee, Wisconsin; zCentre for the Heart and Mind, Australian Catholic University,
Melbourne, Australia; xNational Centre of Rehabilitation and Palliation, University Hospital Odense, and University of Southern
Listen to this manuscript’s
Denmark, Odense, Denmark; kDivision of Health Sciences, Warwick Medical School, University of Warwick, Coventry, United
audio summary by
Kingdom; and the {Department of Non-Communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine,
JACC Editor-in-Chief
London, United Kingdom. Dr. Anderson is funded by the University of Exeter Medical School. Prof. Taylor is partly funded by the
Dr. Valentin Fuster.
U.K. National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care South West
Peninsula at the Royal Devon and Exeter NHS Foundation Trust; and is currently the cochief investigator of a research program
with the overarching aims of developing and evaluating a home-based cardiac rehabilitation intervention for people with heart
failure and their careers (PGfAR RP-PG-0611-12004). Dr. Rees is supported by the NIHR Collaboration for Leadership in Applied
Health Research and Care West Midlands at University Hospitals Birmingham NHS Foundation Trust. Dr. Zwisler is principal
investigator of an included (DAHREHAB) and ongoing cardiac rehabilitation trials (CopenHeart trials). Prof. Taylor, Drs. Rees and
2 Anderson et al.
Exercise for Coronary Heart Disease: Systematic Review
W
ABBREVIATIONS ith increasing numbers of peo-
AND ACRONYMS ple living longer with symptom-
atic coronary heart
CABG = coronary artery bypass
(CHD), the effectiveness and accessibility of
graft
health services for people with CHD have
CHD = coronary heart disease
never been more important. Cardiac rehabil-
CI = confidence interval
itation (CR) programs are recognized as inte-
CR = cardiac rehabilitation
gral to comprehensive care of CHD patients
CV = cardiovascular
and have been given a Class I recommenda-
HRQL = health-related quality
tion from the American Heart Association,
of life
the American College of Cardiology, and the
MI = myocardial infarction
European Society of Cardiology, with exer-
PCI = percutaneous coronary
cise therapy consistently identified as a
intervention
central element (1–4). Although exercise
RCT = randomized controlled
training remains a cornerstone intervention,
trial
international guidelines consistently recom-
RR = relative risk
mend the provision of comprehensive reha-
bilitation that includes education and psychological
input focusing on health and life-style behavior
change, risk factor modification, and psychosocial
well-being (1–3).
SEE PAGE 13
The first systematic reviews and meta-analyses of
exercise-based CR by Oldridge et al. (5) and O’Connor
et al. (6) were published more than 20 years ago,
showing a 20% to 25% reduction in all-cause and car-
diovascular (CV) mortality on the basis of data from 22
randomized controlled trials (RCTs) in over 4,300 pa-
tients. Although there have been more recent updates
to these meta-analyses (7–9), concerns have been
raised about the applicability of their results to policy
planning and the provision of CR services (10,11). It has
been argued that major advances in CHD medical
management may have led to a reduction in the in-
cremental effect on mortality of exercise-based CR
compared with usual care alone. Other concerns have
included the inclusion of small, poor-quality RCTs,
which may have resulted in overestimation of the
benefits of CR, and the almost exclusive recruitment of
low-risk, middle-aged, post-myocardial infarction
(MI) men in early trials, thereby reducing the general-
izability of their findings to the broader population of
CHD patients (12). Our aim was to systematically up-
date existing meta-analyses to reassess the effects of
exercise-based CR in patients with CHD in terms of
mortality, morbidity, health-related quality of life
Oldridge, and Prof. Thompson were authors of the original Cochrane review; and Prof. Taylor and Drs. Rees and Zwisler are
authors on a number of other Cochrane cardiac rehabilitation reviews. The views expressed in this publication are those of the
authors and not necessarily those of the NHS, the NIHR, or the Department of Health in England. Ms. Martin has reported that she
has no relationships relevant to the contents of this paper to disclose.
Manuscript received July 14, 2015; revised manuscript received October 12, 2015, accepted October 14, 2015.
JACC VOL. 67, NO. 1, 2016
JANUARY 5/12, 2016:1–12
(HRQL), and cost-effectiveness. We also sought to
explore whether effects vary with patient case mix, the
disease nature of CR programs, and study characteristics.
METHODS
We conducted and reported this systematic review in
accordance with the PRISMA (Preferred Reporting
Items for Systematic Reviews and Meta-Analyses)
statement (13) and the Cochrane Handbook for
Interventional Reviews (14). The protocol was pub-
lished on the Cochrane Database of Systematic
Reviews (2001) (15).
DATA SEARCHES AND SOURCES. Search terms from
the 2011 Cochrane review (9) were updated and
CENTRAL (Cochrane Central Register of Controlled
Trials), DARE (Database of Abstracts of Reviews of
Effects), HTA (Health Technology Assessment),
MEDLINE and Medline in Process (Ovid), EMBASE
(Ovid), and CINAHL (Cumulative Index to Nursing and
Allied Health Literature) Plus (EBSCO) were searched
to July 2014. Conference proceedings were searched
on the Web of Science Core Collection (Thomson
Reuters) (1970 to June 2014), and bibliographies of
systematic reviews and trial registers (the World
Health Organization [WHO]’s International Clinical
Trials Registry Platform [ICTRP] and Clinicaltrials.gov)
were hand-searched. No language or other limitations
were imposed (see Online Appendix).
STUDY SELECTION. Randomized controlled trials
were sought that compared exercise-based CR with a
control and had a follow-up period of at least 6 months.
Exercise-based CR was defined as a supervised or un-
supervised inpatient, outpatient, community-based,
or home-based intervention that included some form
of exercise training, either alone or in addition to
psychosocial and/or educational interventions. The
comparator could include standard medical care and
psychosocial and/or educational interventions, but
not any structured exercise training. We included pa-
tients irrespective of sex or age who had an MI, had
undergone revascularization (coronary artery bypass
grafting [CABG] or percutaneous coronary interven-
tion [PCI]), or who have angina pectoris or CHD defined
by angiography. Finally, studies needed to report 1 or
more of the following outcomes: total or CV mortality;
fatal or nonfatal MI; revascularizations (CABG or PCI);
JACC VOL. 67, NO. 1, 2016 Anderson et al. 3
JANUARY 5/12, 2016:1–12 Exercise for Coronary Heart Disease: Systematic Review

F I G U R E 1 Summary of Study Selection Process

RCTs included from 2011 Cochrane

Titles identified from electronic bibliographies &
review
screened for retrieval
N = 47
N = 11,028
(N = 81 publications)

Excluded
N = 10,937

Potentially appropriate full-text publications

retrieved for full evaluation
N = 91
Excluded
- 2 ongoing studies
- 3 studies awaiting classification
- 65 excluded
follow-up < 6 months N = 11;
RCTs from updated search inappropriate comparator N=12;
N = 16 inappropriate outcomes N=16;
(N = 21 publications) inappropriate randomization N=15;
inappropriate intervention N=7;
inappropriate population N=2;
population had previously received CR N=2

Total RCTs included in review

N = 63
(N = 102 Publications)

The 63 studies in this review included 47 studies (81 publications) from the 2011 version of the review, and a further 16 studies (21 publications) identified
from the updated searches. RCT ¼ randomized controlled trial.

hospitalizations; HRQL, assessed using validated in-
struments; or costs and cost-effectiveness. Two re-
viewers (L.A. and R.S.T.) independently assessed all
identified titles/abstracts for possible inclusion, with
any disagreements resolved by discussion. Where
necessary, studies were translated into English.
DATA EXTRACTION AND MANAGEMENT. One
reviewer (L.A.) extracted study and patient charac-
teristics, intervention and comparator details, and
outcome data from included studies using a stan-
dardized data collection form. A second author
(R.S.T.) checked for accuracy, and disagreements
were resolved by consensus. Duplicate publications
of the same study were assessed for additional data
and authors were contacted, where necessary, to
provide additional information.
ASSESSMENT OF RISK OF BIAS AND OVERALL
QUALITY OF EVIDENCE. Risk of bias of included
studies was assessed using the Cochrane Collabo-
ration’s core risk of bias items (14) and 3 further
items deemed relevant to this review. GRADEProfiler
software (16) was used to assess the overall quality of
evidence for each outcome collected (17) (see the
Online Appendix for full details).
DATA SYNTHESIS AND ANALYSIS. Dichotomous
outcomes were expressed as relative risks (RRs) with
95% confidence intervals (CIs). HRQL scores were
expressed as mean differences. Heterogeneity among
included studies was explored qualitatively and
quantitatively (using the chi-square test of hetero-
geneity and I 2 statistic). Data from each study
were pooled using a conservative random effects
meta-analysis model.
The meta-analysis of each outcome was stratified
according to the duration of study follow-up (i.e., 6 to
12 months [short-term]; 13 to 36 months [medium-
term]; and >36 months [long-term]). Using the
longest follow-up, we stratified meta-analyses to
explore heterogeneity and examine potential treat-
ment effect modifiers. We tested 9 a priori hypotheses
that there may be differences in the effect of exercise-
based CR on outcomes at longest follow-up across the
4 Anderson et al. JACC VOL. 67, NO. 1, 2016

Exercise for Coronary Heart Disease: Systematic Review JANUARY 5/12, 2016:1–12

<1,000 U); 4) follow-up period; 5) year of publication;

T A B L E 1 Summary of Trial and Patient Characteristics (63 Included Studies)
6) sample size; 7) setting (home- or center-based CR);
Study characteristics
8) risk of bias (low risk of bias in <5 of 8 domains);
Publication year
and 9) study location (continent).
1970–1979 2 (3)
1980–1989 12 (19) The funnel plot and Egger test were used to
1990–1999 20 (32) examine small-study bias (18). All statistical analyses
2000–2009 21 (33) were performed using Review Manager 5.3 Software
2010 onwards 8 (13) (19) and STATA version 13.0 (StataCorp, College
Study location Station, Texas) (20).
Europe 37 (59)
North America 12 (19)
RESULTS
Asia 6 (10)
Australasia 5 (8)
Other 2 (3) SELECTION AND INCLUSION OF STUDIES. The 2011
Not reported 1 (2) Cochrane review provided 47 RCTs (81 publications).
Single center 45 (71) Our searches for this update yielded 11,028 titles, of
Sample size 126 (28–2,304) which 91 full papers were considered for inclusion.
Duration of follow-up, months 12 (6–120)
Sixteen new RCTs (21 publications) were included,
Population characteristics
giving a total of 63 studies (102 publications; see
Sex
Figure 1 for a summary of the study selection process
Males only 18 (29)
Females only 1 (2)
and Online Table 1 for a list of included studies).
Both males and female 41 (65) STUDY, PATIENT, AND INTERVENTION CHARACTERISTICS.
Not reported 3 (5) Fourteen studies were published before 1999, and
Age, yrs 56.0 (49.3–71.0) 49 have been published since 2000 (Table 1). The me-
Diagnosis dian follow-up was 12 months, with 50 studies
Post-myocardial infarction only 31 (49)
reporting at least 12 months of follow-up, and 18
Revascularization only 2 (3)
reporting follow-up of 36 months or more. The major-
Angina only 5 (8)
ity of studies were conducted in Europe (37 studies) or
Mixed CHD population 25 (40)
Intervention characteristics North America (12 studies). Although we included
Intervention type 14,486 patients, most studies were small in sample size
Exercise-only programs 25* (38) (median n ¼ 126; range 28 to 2,304), with 2 large
Comprehensive programs 39* (60) multicenter trials (WHO and RAMIT [Rehabilitation
Duration of intervention, months 6 (1–48) After Myocardial Infarction Trial]) (12,21) contributing
Dose of intervention
a total of 4,177 patients (about 30% of all participants).
Duration 6 months (1–48)
The median age of participants across studies was
Frequency 1–7 sessions/week
Length 20–90 min/session
56.0 years. Although 42 studies (66%) included
Intensity  50%–85% of maximal heart rate women, they accounted for <15% of all patients
 50%–95% of maximal oxygen uptake recruited. Studies published since 2005 were less
(VO2 max)
 Borg rating of 11–15 dominated by post-MI patients, included other CHD
Setting diagnoses (such as revascularization and angina), and
Center-based only 33 (52) were more likely to include older (average mean age
Combination of center- and 13 (21) 61.7 years vs. 56.3 years) and female (20.0% vs. 12.5%)
home-based
participants.
Home-based only 15 (24)
Not reported 2 (3) Exercise-based CR programs were typically deliv-
ered in a supervised hospital/center-based setting,
Values are number of studies (%) or median (range). Median of study means: *1 study includes either exclusively or in combination with some
both exercise-only and comprehensive cardiac rehabilitation arms.
CHD ¼ coronary heart disease. maintenance home exercise sessions. Fifteen studies
were conducted in an exclusively home-based setting
(22–36). Whereas the primary mode of exercise
following subgroups: 1) CHD case mix (MI-only trials training across all studies was aerobic, the overall or
vs. other trials); 2) type of CR (exercise-only CR vs. average duration, frequency, and intensity of ses-
comprehensive CR); 3) dose of exercise intervention sions varied considerably across studies. A total of 24
(dose ¼ number of weeks of exercise training  studies were exercise-only programs, 38 were
average number of sessions/week  average duration comprehensive CR, and 1 trial included both exercise-
of session in minutes) (dose $1,000 U vs. dose only and comprehensive CR arms (37).
JACC VOL. 67, NO. 1, 2016 Anderson et al. 5
JANUARY 5/12, 2016:1–12 Exercise for Coronary Heart Disease: Systematic Review

T A B L E 2 Summary of Meta-Analysis Effects of Exercise-Based CR on Clinical Event Outcomes

Number of Events/
Statistical Heterogeneity I2
Participants
Number of Participants Statistic Chi-Square Test GRADE Quality
Outcome (Number of Studies) Intervention Comparator RR (95% CI) (p Value) of the Evidence

All-cause mortality (all studies) 12,455 (47) 838/6,424 865/6,031 0.96 (0.88–1.04) 0% (0.58) þþþ
moderate*
Follow-up 6–12 months 8,800 (29) 226/4,573 238/4,227 0.88 (0.73–1.05) 0% (0.82)
Follow-up >12–36 months 6,823 (13) 338/3,495 417/3,328 0.89 (0.78–1.01) 0% (0.47)
Follow-up longer than 3 yrs 3,828 (11) 476/1,902 493/1,926 0.91 (0.75–1.10) 35% (0.12)
CV mortality (all studies) 7,469 (27) 292/3,850 375/3,619 0.74 (0.64–0.86) 0% (0.70) þþþ
moderate*
Follow-up 6–12 months 4,884 (15) 105/2,561 107/2,323 0.90 (0.69–1.17) 0% (0.72)
Follow-up >12–36 months 3,833 (7) 199/1,971 239/1,862 0.77 (0.63–0.93) 5% (0.38)
Follow-up longer than 3 yrs 1,392 (8) 56/690 100/702 0.58 (0.43–0.78) 0% (0.91)
Fatal and/or nonfatal MI (all studies) 9,717 (36) 356/4,951 387/4,766 0.90 (0.79–1.04) 0% (0.48) þþ
low*†
Follow-up 6–12 months 6,911 (20) 126/3,543 139/3,368 0.85 (0.67–1.08) 0% (0.58)
Follow-up >12–36 months 5,644 (11) 251/2,877 222/2,767 1.09 (0.91–1.29) 0% (0.72)
Follow-up longer than 3 yrs 1,560 (10) 65/776 102/784 0.67 (0.50–0.90) 0% (0.67)
CABG (all studies) 5,891 (29) 208/3,021 212/2,870 0.96 (0.80–1.16) 0% (0.86) þþþ
moderate*
Follow-up 6–12 months 4,563 (21) 123/2,351 121/2,212 0.99 (0.77–1.26) 0% (0.83)
Follow-up >12–36 months 2,755 (98) 122/1,379 123/1,376 0.98 (0.78–1.25) 0% (0.93)
Follow-up longer than 3 yrs 675 (4) 19/333 29/342 0.66 (0.34–1.27) 18% (0.30)
PCI (all studies) 4,012 (16) 171/2013 197/1999 0.85 (0.70–1.04) 0% (0.59) þþþ
moderate*
Follow-up 6–12 months 3,564 (13) 90/1,778 99/1,786 0.92 (0.64–1.33) 16% (0.30)
Follow-up >12–36 months 1,983 (6) 114/996 116/987 0.96 (0.69–1.35) 26% (0.24)
Follow-up longer than 3 yrs 567 (3) 28/281 37/286 0.76 (0.48–1.20) 0% (0.81)
Hospital admissions (all studies) 3,030 (15) 407/1,556 453/1,474 0.82 (0.70–0.96) 34.5% (0.10) þþ
low*†
Follow-up of 6–12 months 1,120 (9) 82/574 116/546 0.65 (0.46–0.92) 37% (0.14)
Follow-up >12–36 months 1,916 (6) 322/984 330/932 0.95 (0.84–1.07) 0% (0.50)
Follow-up longer than 3 yrs 0 (0) 0/0 0/0 Not estimable Not estimable

*Random sequence generation, allocation concealment, or blinding of outcome assessors were poorly described in >50% of included studies; bias likely. †Funnel plots and/or Egger test suggest evidence of
asymmetry. GRADE Working Group grades of evidence: high ¼ further research is very unlikely to change our confidence in the estimate of effect; moderate ¼ further research is likely to have an important
effect on our confidence in the estimate of effect and may change the estimate; low ¼ further research is very likely to have an important effect on our confidence in the estimate of effect and is likely to
change the estimate. Very low quality: we are very uncertain about the estimate.
CABG ¼ coronary artery bypass graft; CI ¼ confidence interval; CR ¼ cardiac rehabilitation; CV ¼ cardiovascular; MI ¼ myocardial infarction; PCI ¼ percutaneous coronary intervention; RR ¼ relative risk.

RISK OF BIAS AND GRADE ASSESSMENT. The overall
risk of bias across domains was judged to be low or
unclear (Online Table 2). Quality of reporting was
generally higher in more recent studies. Overall, the
GRADE (Grading of Recommendations Assessment,
Development and Evaluation) quality of evidence for
each outcome was assessed as low to moderate
(Table 2).
OUTCOME RESULTS. As there was no difference in
the effect of exercise-based CR on clinical outcomes
across length of follow-up (Table 2), the following
results focus on pooled findings across all trials at
their longest follow-up (median 12 months).
M o r t a l i t y . Forty-seven studies (n ¼ 12,455) reported
total mortality (Table 2, Figure 2). There was no sta-
tistically significant reduction in total mortality with
exercise-based CR (RR: 0.96; 95% CI: 0.88 to 1.04)
compared with no-exercise control subjects. Twenty-
seven studies (n ¼ 7,469) reported CV mortality
(Table 2, Central Illustration, Figure 3), and a statisti-
cally significant reduction in this outcome was seen
with the no-exercise control subjects (RR: 0.74;
95% CI: 0.64 to 0.86). Twenty studies reported both
mortality outcomes. Results for mortality outcomes
in this subgroup were consistent with the overall
meta-analysis results (all-cause mortality RR: 0.91,
95% CI: 0.82 to 1.01; CV mortality RR: 0.78,
95% CI: 0.67 to 0.90).
M o r b i d i t y . Thirty-six studies (n ¼ 9,717) reported
the risk of fatal or nonfatal MI (Table 2, Online
Figure 1), and no statistically significant difference
in the risk of total MI was found with exercise-based
CR (RR: 0.90; 95% CI: 0.79 to 1.04). Twenty-nine
(n ¼ 5,891), and 16 (n ¼ 4,012) studies reported the
risk of CABG and PCI, respectively (Table 2, Online
Figures 2 and 3). There was no difference between
6 Anderson et al. JACC VOL. 67, NO. 1, 2016

Exercise for Coronary Heart Disease: Systematic Review JANUARY 5/12, 2016:1–12

F I G U R E 2 Exercise-Based Rehabilitation Versus Usual Care: Total Mortality

Study Relative risk Events, Events,

ID random (95% CI) Treatment Control

Wilhelmsen 75 0.79 (0.51, 1.24) 28/158 35/157

Kallio 79 0.73 (0.51, 1.03) 41/188 56/187
Andersen 81 1.22 (0.29, 5.12) 4/46 3/42
Sivarajan 82b 1.50 (0.16, 13.93) 3/74 1/37
Carson 82 0.58 (0.29, 1.13) 12/151 21/152
Sivarajan 82a 1.37 (0.15, 12.70) 3/79 1/36
Bengtsson 83 1.85 (0.70, 4.87) 10/81 6/90
WHO 83 0.91 (0.75, 1.10) 169/1208 169/1096
Vermeulen 83 0.43 (0.09, 2.13) 2/47 5/51
Roman 83 0.64 (0.37, 1.10) 16/93 27/100
Stern 83 0.23 (0.01, 5.52) 0/42 1/29
Erdman 86 9.00 (0.50, 161.86) 4/40 0/40
Bethell 90 1.37 (0.68, 2.76) 16/113 12/116
Fridlund 91 0.67 (0.31, 1.47) 9/87 14/91
Leizorovicz (PRECOR) 91 0.11 (0.01, 2.05) 0/60 4/61
Oldridge 91 0.77 (0.18, 3.36) 3/99 4/102
Bertie 92 0.13 (0.01, 2.52) 0/57 3/53
Schuler 92 2.04 (0.19, 21.82) 2/56 1/57
Engblom 92 0.85 (0.40, 1.77) 12/119 13/109
Heller 93 2.23 (0.56, 8.79) 6/213 3/237
Fletcher 94 0.86 (0.20, 3.62) 3/41 4/47
Holmback 94 1.03 (0.07, 15.80) 1/34 1/35
Debusk 94 1.20 (0.52, 2.72) 12/293 10/292
Haskell (SCRIP) 94 1.07 (0.22, 5.21) 3/145 3/155
Carlsson 98 0.99 (0.14, 6.91) 2/113 2/112
Bell 98 0.97 (0.44, 2.13) 19/251 8/102
Stahle 99 1.58 (0.40, 6.28) 5/56 3/53
Hofman-Bang 99 0.15 (0.02, 1.18) 1/46 6/41
Dorn (NEHDP) 99 1.09 (0.93, 1.28) 162/315 150/319
Toobert 00 2.00 (0.09, 45.12) 1/17 0/11
Higgins 01 2.73 (0.11, 65.43) 1/54 0/49
VHSG 03 2.02 (0.19, 21.92) 2/98 1/99
Yu 04 0.55 (0.14, 2.12) 4/132 4/72
Hambrecht 04 0.49 (0.05, 5.24) 1/51 2/50
Montero 05 0.44 (0.19, 1.01) 7/90 16/90
Briffa 05 0.20 (0.01, 4.00) 0/57 2/56
Zwisler 08 1.16 (0.66, 2.03) 24/227 20/219
Reid 11 0.19 (0.01, 3.87) 0/115 2/108
West (RAMIT) 12 1.02 (0.87, 1.18) 245/903 243/910
Mutwalli 12 0.25 (0.01, 5.91) 0/28 1/21
Wang 12 0.33 (0.04, 3.14) 1/80 3/80
Oerkild 12 0.88 (0.28, 2.82) 4/19 5/21
Manchanda 00 (Excluded) 0/21 0/21
Kovoor 06 (Excluded) 0/72 0/70
Seki 08 (Excluded) 0/18 0/16
Munk 09 (Excluded) 0/20 0/20
Houle 12 (Excluded) 0/32 0/33
Maddison 14 (Excluded) 0/85 0/86
Overall (I-squared = 0.0%, p = 0.584) 0.96 (0.88, 1.04) 838/6424 865/6031
NOTE: Weights are from random effects analysis

.1 1 10
Favors CR Favors control

The boxes are proportional to the weight of each study in the analysis, and the lines represent their 95% confidence intervals (CIs). The open diamond
represents the pooled relative risk, and its width represents its 95% CI. CR ¼ cardiac rehabilitation.

exercise CR and usual care for either CABG or PCI
(CABG: RR: 0.96, 95% CI: 0.80 to 1.16; PCI: RR: 0.85,
95% CI: 0.70 to 1.04). Fifteen studies (n ¼ 3,030)
reported hospital admissions (Table
Illustration, Figure 3). Risk of admissions was reduced
with exercise-based CR compared with usual care
(RR: 0.82, 95% CI: 0.70 to 0.96, random effects). There
was no evidence of statistical heterogeneity across
trials in either mortality or morbidity outcomes (with
exception of hospitalizations) (I 2 statistic: 35%).
S t r a t i fi e d m e t a - a n a l y s e s . There was no evidence of
2, Central difference in CR versus control treatment effects ac-
ross mortality and morbidity outcomes across any pa-
tient, intervention, or study characteristics (Table 3).
H e a l t h - r e l a t e d q u a l i t y o f l i f e . Twenty studies
(n ¼ 5,060) assessed HRQL using a range of validated
JACC VOL. 67, NO. 1, 2016 Anderson et al. 7
JANUARY 5/12, 2016:1–12 Exercise for Coronary Heart Disease: Systematic Review

CENTRAL I LLU ST RAT ION Exercise-Based Cardiac Rehabilitation for Coronary Heart Disease Versus Usual Care:
CV Mortality and Hospitalization

Anderson, L. et al. J Am Coll Cardiol. 2016; 67(1):1–12.

Box sizes are proportional to the weight of each study in the analysis, and the lines represent their 95% confidence intervals (CIs). The open
diamond represents the pooled RR, and its width represents its 95% CI. CV ¼ cardiovascular.
8 Anderson et al. JACC VOL. 67, NO. 1, 2016

Exercise for Coronary Heart Disease: Systematic Review JANUARY 5/12, 2016:1–12

T A B L E 3 Stratified Meta-Analysis by Patient, Intervention, and Study Characteristics at Longest Follow-Up

All-Cause Mortality CV Mortality MI CABG PCI Hospitalization

All studies 0.96 (0.88–1.04) 0.74 (0.64–0.86) 0.90 (0.79–1.04) 0.96 (0.80–1.16) 0.85 (0.70–1.04) 0.82 (0.70–0.96)
Case mix
100% MI 0.89 (0.78–1.01) 0.75 (0.65–0.87) 0.89 (0.76–1.05) 0.67 (0.45–1.00) 0.87 (0.67–1.15) 0.71 (0.41–1.24)
<100% MI 1.06 (0.92–1.22) 0.63 (0.38–1.06) 0.73 (0.44–1.23) 1.06 (0.86–1.31) 0.82 (0.58–1.15) 0.82 (0.68–0.99)
Dose of exercise*
<1,000 0.89 (0.26–3.15) 0.47 (0.19–1.15) 0.72 (0.30–1.70) 0.96 (0.35–2.66) 1.22 (0.34–4.34) 0.70 (0.48–1.00)
$1,000 1.01 (0.89–1.15) 0.75 (0.65–0.86) 0.74 (0.59–0.93) 0.99 (0.78–1.27) 0.80 (0.62–1.03) 0.85 (0.71–1.01)
Type of CR
Exercise only 0.94 (0.77–1.16) 0.65 (0.50–0.85) 0.76 (0.60–0.98) 0.98 (0.68–1.42) 0.87 (0.35–2.17) 0.61 (0.33–1.14)
Comprehensive CR 0.93 (0.841–1.03) 0.79 (0.66–0.94) 0.90 (0.72–1.14) 0.96 (0.77–1.19) 0.87 (0.71–1.07) 0.85 (0.72–1.00)
Duration of follow-up
#12 months 1.08 (0.51–2.33) 0.72 (0.62–0.84) 0.60 (0.39–0.91) 1.03 (0.74–1.44) 0.83 (0.54–1.27) 0.63 (0.46–0.88)
>12 months 0.96 (0.88–1.04) 1.00 (0.63–1.60) 0.92 (0.77–1.09) 0.93 (0.75–1.17) 0.84 (0.64–1.09) 0.92 (0.80–1.05)
Year of publication
Pre-1995 0.85 (0.75–0.98) 0.78 (0.67–0.91) 0.96 (0.81–1.14) 0.87 (0.59–1.30) 0.80 (0.42–1.51) 0.85 (0.69–1.05)
Post-1995 1.03 (0.903–1.14) 0.56 (0.38–0.83) 0.76 (0.59–0.99) 0.99 (0.81–1.22) 0.86 (0.70–1.06) 0.78 (0.60–1.00)
Setting
Center 0.91 (0.80–1.04) 0.75 (0.65–0.87) 0.96 (0.83–1.11) 0.97 (0.77–1.23) 0.90 (0.60–1.35) 0.89 (0.76–1.04)
Center þ home 0.78 (0.40–1.53) 0.67 (0.30–1.47) 0.40 (0.14–1.11) 0.79 (0.44–1.44) 0.65 (0.37–1.14) 0.83 (0.46–1.50)
Home 1.02 (0.68–1.54) 0.87 (0.34–2.20) 0.48 (0.28–0.83) 1.01 (0.59–1.7) 0.79 (0.53–0.18) 0.60 (0.33–1.05)
Risk of bias
Low (bias in <5 of 8 domains) 1.01 (0.88–1.17) 0.91 (0.22–3.74) 0.96 (0.69–1.33) 0.92 (0.69–1.21) 0.91 (0.70–1.18) 0.85 (0.61–1.20)
High (bias in >5 of 8 domains) 0.90 (0.80–1.02) 0.74 (0.64–0.86) 0.83 (0.69–1.00) 1.00 (0.79–1.28) 0.79 (0.59–1.06) 0.79 (0.65–0.97)
Study location, continent
Europe 0.90 (0.80–1.02) 0.73 (0.62–0.87) 0.93 (0.79–1.09) 0.94 (0.74–1.19) 0.85 (0.65–1.13) 0.72 (0.56–0.92)
North America 1.10 (0.94–1.27) 0.89 (0.56–1.43) 0.62 (0.41–0.94) 1.05 (0.78–1.42) 0.78 (0.52–1.16) 0.95 (0.81–1.11)
Australasia 0.85 (0.35–2.07) 0.33 (0.01–7.88) 1.90 (0.33–10.72) 0.32 (0.07–1.55) 0.99 (0.32–3.02) 1.07 (0.74–1.54)
Other 0.62 (0.36–1.07) 0.58 (0.32–1.08) 0.25 (0.01–5.91) NR NR 0.27 (0.10–0.74)
Sample size
#150 0.81 (0.51–1.29) 0.58 (0.33–1.00) 0.54 (0.35–0.83) 0.78 (0.53–1.16) 0.82 (0.47–1.42) 0.60 (0.46–0.78)
>150 0.95 (0.86–1.05) 0.76 (0.65–0.88) 0.93 (0.78–1.11) 1.02 (0.83–1.26) 0.87 (0.70–1.08) 0.93 (0.83–1.05)

Values are relative risk (95% confidence interval). *Number of weeks of exercise training  average number of sessions/week  average duration of session in minutes.
NR ¼ not measurable; other abbreviations as in Table 2.

generic or disease-specific outcome measures (Online $42,535/quality-adjusted life-year (40) for CR to a

Table 3). Given the heterogeneity in both outcome
measures and methods of reporting the findings, we
did not undertake meta-analysis. Fourteen of the 20
studies (65%) reported a higher level of HRQL in 1 or
more subscales following exercise-based CR compared
with control subjects (23,27,29,31,33,35,36,38–44), and
in 5 studies (25%), there was a higher level of HRQL in
one-half or more of the subscales (23,33,35,36,38).
C o s t s a n d c o s t - e f f e c t i v e n e s s . Seven studies re-
ported data on costs (31,40,45–49) (Online Table 4).
Three studies showed no difference in total health
care costs between CR and control groups (40,45,47),
1 reported lower health care costs for CR compared
with usual care (reduction of U.S. $2,378/patient)
(48), another reported higher health care costs for CR
(increase of U.S. $4,839/patient) (46), and 2 studies
did not report total health care costs (31,49).
Cost-effectiveness ranged from an additional U.S.
reduction of U.S. $650/quality-adjusted life-year (47)
for CR compared with control subjects.
SMALL STUDY BIAS. There was no evidence of funnel
plot asymmetry or significant Egger tests for mortal-
ity or revascularization outcomes (Online Figures 4
to 7). However, Egger tests were significant for MI
(p ¼ 0.009) and hospitalization (p ¼ 0.001), indicating
funnel plot asymmetry. This asymmetry appeared to
be due to an absence of small- to medium-sized
studies with negative results for exercise-based CR
(Online Figures 8 and 9).
DISCUSSION
We conducted an updated systematic review and
meta-analysis of exercise-based CR in people with
existing CHD. Our study shows a reduction in pooled
CV mortality (10.4% to 7.6%; number needed to treat:
JACC VOL. 67, NO. 1, 2016 Anderson et al. 9
JANUARY 5/12, 2016:1–12 Exercise for Coronary Heart Disease: Systematic Review

F I G U R E 3 Exercise-Based Rehabilitation Versus Usual Care: Cardiovascular Mortality and Hospitalization

Exercise-based rehabilitation versus usual care: cardiovascular mortality

Study Relative risk Events, Events,
ID random (95% CI) Treatment Control

Wilhelmsen 75 0.69 (0.43, 1.12) 23/158 33/157

Kallio 79 0.63 (0.44, 0.92) 35/188 55/187
Shaw (NEDHP) 81 0.71 (0.37, 1.38) 14/323 20/328
Vecchio 81 0.20 (0.01, 3.97) 0/25 2/25
Sivarajan 82a 1.35 (0.15, 12.50) 3/71 1/32
Sivarajan 82b 3.61 (0.19, 67.81) 3/65 0/33
Vermeulen 83 0.43 (0.09, 2.13) 2/47 5/51
Roman 83 0.58 (0.32, 1.08) 13/93 24/100
WHO 83 0.87 (0.70, 1.07) 144/1208 151/1096
Haskell (SCRIP) 84 0.71 (0.12, 4.20) 2/145 3/155
Miller 84 0.11 (0.01, 2.31) 0/127 2/71
Bethell 90 1.11 (0.53, 2.33) 13/113 12/116
Ornish 90 1.43 (0.14, 14.70) 2/28 1/20
Schuler 92 5.09 (0.25, 103.66) 2/56 0/57
Debusk 94 1.22 (0.51, 2.90) 11/293 9/292
Specchia 96 0.40 (0.15, 1.10) 5/125 13/131
Hofman-Bang 99 0.15 (0.02, 1.18) 1/46 6/41
Dugmore 99 0.67 (0.12, 3.85) 2/62 3/62
Toobert 00 2.00 (0.09, 45.12) 1/17 0/11
La Rovere 02 0.47 (0.19, 1.15) 6/49 12/46
Hambrecht 04 0.20 (0.01, 3.99) 0/51 2/50
Briffa 05 0.33 (0.01, 7.87) 0/57 1/56
Montero 05 0.50 (0.21, 1.18) 7/90 14/90
Aronov 10 0.49 (0.13, 1.95) 3/197 6/195
Belardinelli 01 (Excluded) 0/59 0/59
Seki 08 (Excluded) 0/20 0/19
Munk 09 (Excluded) 0/20 0/20
Houle 12 (Excluded) 0/32 0/33
Maddison 14 (Excluded) 0/85 0/86
Overall (I-squared = 0.0%, p = 0.699) 0.74 (0.64, 0.86) 292/3850 375/3619
NOTE: Weights are from random effects analysis

.1 1 10
Favors CR Favors control

Exercise-based rehabilitation versus usual care: hospitalization

Study Relative risk Events, Events,
ID random (95% CI) Treatment Control

Shaw (NEDHP) 81 0.98 (0.79, 1.21) 109/323 113/328

Lewin 92 0.50 (0.25, 1.02) 9/58 18/58

Haskell 94 0.92 (0.71, 1.19) 62/145 72/155

Engblom 96 0.68 (0.45, 1.04) 26/102 34/91

Hofman-Bang 99 0.81 (0.51, 1.27) 19/46 21/41

Belardinelli 01 0.52 (0.28, 0.99) 11/59 21/59

VHSG 03 0.79 (0.38, 1.66) 11/98 14/99

Yu 04 1.16 (0.69, 1.95) 34/132 16/72

Hambrecht 04 0.14 (0.02, 1.10) 1/51 7/50

Briffa 05 0.98 (0.59, 1.65) 19/57 19/56

Giallauria 08 0.44 (0.13, 1.55) 3/30 7/31

Zwisler 08 0.98 (0.79, 1.21) 95/227 94/219

Reid 11 0.63 (0.18, 2.16) 4/115 6/108

Mutwalli 12 0.27 (0.10, 0.74) 4/28 11/21

Maddison 14 (Excluded) 0/85 0/86

Overall (I-squared = 34.5%, p = 0.099) 0.82 (0.70, 0.96) 407/1556 453/1474

NOTE: Weights are from random effects analysis

.1 1 10
Favors CR Favors control

Filled diamonds represent the relative risk for individual studies at the longest reported follow-up. The boxes are proportional to the weight of
each study in the analysis, and the lines represent their 95% confidence interval (CIs). The open diamond represents the pooled relative risk,
and its width represents its 95% CI.
10 Anderson et al.
Exercise for Coronary Heart Disease: Systematic Review
37), and hospital admission (30.7% to 26.1%; number
needed to treat: 22) with exercise-based CR compared
with no-exercise control subjects. There was no
between-group difference in total mortality or the
risk of fatal or nonfatal MI, CABG, or PCI. Outcome
effects were consistent across RCTs, irrespective
of patient case mix (i.e., % of MI patients), the
nature of the CR program (i.e., exercise-only or
comprehensive CR, dose of exercise training, or cen-
ter- or home-based settings), and study characteris-
tics (i.e., sample size, risk of bias, location, length
of follow-up, or year of publication). There was
evidence of higher levels of HRQL following exercise-
based CR compared with control subjects, and also
that exercise-based CR can be a cost-effective use of
health care resources.
In contrast to previous meta-analyses, we did
not observe a statistically significant reduction in
all-cause mortality with exercise-based CR. This may
be explained by the inclusion of more recent studies
that include a more mixed population of CHD pa-
tients, conducted in the era of optimal medical
therapy for CHD. Our review included RCTs con-
ducted over a period (1974 to 2014) during which
there have been a number of major advances in
medical CHD management, such as the increased
use of statins. We found some support for this
hypothesis in our meta-regression analysis, which
shows a trend of a linear reduction (slope: 0.0063;
95% CI: 0.00150 to 0.0141; p ¼ 0.08) in the all-
cause mortality effect (log RR) of CR over time
(i.e., study publication date) (Online Figure 10).
Despite the observed improvements in CV mortality,
in a context of contemporary CHD medical treat-
ments, the opportunity for additional gains in over-
all mortality with exercise-based CR may be small.
Nonetheless, the observation that exercise-based CR
reduces the risk of CV mortality compared with no-
exercise control subjects, but does not reduce the
risk of MI or revascularization, suggests
although CR does not improve coronary vascular
function or integrity, it does confer improved sur-
vival in patients post-MI.
STUDY LIMITATIONS. The generally poor level of
reporting in the included RCTs made it difficult to
assess their methodological quality and thereby
judge their risk of bias. However, we did find some
improvements in the quality of reporting in more
recently published studies. Reassuringly, the find-
ings of our meta-analysis were consistent when
limited to studies with a lower risk of bias. Never-
theless, the general paucity of reporting led us to
downgrade the GRADE quality of evidence for
outcomes to low or moderate. We acknowledge that
JACC VOL. 67, NO. 1, 2016
JANUARY 5/12, 2016:1–12
the median outcome follow-up of 12 months is
limited when assessing the effect on mortality and
morbidity outcome measures. However, our results
were consistent when pooling was limited to RCTs
with a follow up >12 months. Funnel plot asymmetry
for the risk of MI and hospital admission is indicative
of possible publication bias. Included RCTs did not
consistently report all outcomes relevant to this re-
view, and events were often reported in study de-
scriptions of dropout or withdrawal. Our results are,
therefore, on the basis of small and different subsets
of the overall RCT evidence base. However, we found
our overall meta-analysis results to be consistent in
the subgroup of 20 studies reporting both overall and
CV mortality outcomes. The minority of trials re-
ported non-CV causes of death. Only more recent
studies have begun to consistently report data on
hospitalizations, but still often fail to differentiate
between new and recurrent admissions, whereas
HRQL and cost data are still collected infrequently.
Finally, we sought to categorize the diagnoses of
study participants according to a more detailed
framework on the basis of Braunwald’s classification
of CHD (50) to study whether the effect of
exercise-based CR differs according to the pre-
sentation, that is, acute coronary syndrome (MI,
non–ST-segment elevation MI, unstable angina pec-
toris) and stable angina pectoris or treatment mo-
dality (PCI, CABG, or medication alone). The limited
reporting by RCTs of inclusion and exclusion criteria
and participant characteristics prevented us from
applying this categorization. Nevertheless, we
believe this to be the most comprehensive review of
evidence to date, summarizing the results of RCTs in
>14,000 patients.
CONCLUSIONS
Among patients with established CHD, provision of
that exercise-based CR provides important health benefits
that include reductions in CV mortality and hospi-
talization (and associated health care costs) and im-
provements in HRQL. On the basis of a meta-analysis
of RCTs, these results support the Class I recom-
mendation of current international clinical guidelines
that CR should be offered to CHD patients. However,
future trials need to pay increased attention to
recruitment of patients who are more representative
of the broader CHD population, including those at
higher risk, with major comorbidities, and also with
stable angina. Future trials also need to improve their
quality of reporting, particularly in terms of risk of
bias, details of the intervention and control, clinical
events, HRQL, and health economic outcomes.
JACC VOL. 67, NO. 1, 2016
JANUARY 5/12, 2016:1–12
ACKNOWLEDGMENTS The authors
Zhelev, Shenqiu Zhang, and Oriana Ciani for their
translation services, and Harriot
assistance with screening. The authors also thank
all of the authors who provided additional infor-
mation about their trials and the coauthors of
the 2 previous versions of this review. Finally,
the authors thank the Cochrane Heart Group for
their support of the co-publication of this article
with the full version of the review, which is pub-
lished on the Cochrane Database of Systematic
Reviews (51).
REPRINT REQUESTS AND CORRESPONDENCE: Prof.
Rod S. Taylor, Institute of Health Services Research,
University of Exeter Medical School, South Cloisters,
St Luke’s Campus, Exeter EX1 2LU, United Kingdom.
E-mail: r.taylor@exeter.ac.uk.
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KEY WORDS coronary artery bypass graft,
exercise therapy, exercise training,
myocardial infarction, percutaneous
coronary intervention, revascularization
A PPE NDI X For an expanded Methods section
and supplemental figures and tables, please see
the online version of this article.